2-pyrrolin-3-carbonitril-derivatives, pharmaceutical compositions containing them and their anti-inflammatory and ulcer protective activity

ABSTRACT

The present invention provides compounds of the general formula I ##STR1## wherein R 1  and R 2 , which are the same or different, are unsubstituted or substituted aromatic rings, Alk is a straight-chained or branched lower hydrocarbon chain and Z is a hydrogen atom, with the proviso that when Alk is a straight-chained hydrocarbon chain, Z can also be a lower alkylamino radical of the general formula II ##STR2## in which R 3  and R 4  are the same or different and are hydrogen atoms or straight-chained or branched lower alkyl radicals or R 3  and R 4 , together with the nitrogen atom to which they are attached, can also form a ring optionally containing further hetero atoms; and the pharmacologically acceptable salts thereof. 
     The present invention also provides an inventive process for preparing these compounds, as well as pharmaceutical compositions containing them. The compounds I may be used in the therapy of inflammations and they are free of gastrointestinal side effects.

This is a division of application Ser. No. 478,762, filed Mar. 25, 1983,now U.S. Pat. No. 4,517,185, issued May 14, 1985.

The present invention is concerned with new5-oxo-2-pyrroline-3-carbonitriles, with the preparation thereof and withpharmaceutical compositions containing them.

The new 5-oxo-2-pyrroline-3-carbonitriles according to the presentinvention are compounds of the general formula: ##STR3## wherein R¹ andR², which can be the same or different, are unsubstituted or substitutedaromatic rings, Alk is a straight-chained or branched lower hydrocarbonchain and Z is a hydrogen atom, with the proviso that when Alk is astraight-chained hydrocarbon chain, Z can also be an Amino radical ofthe general formula: ##STR4## in which R³ and R⁴ are the same ordifferent and are hydrogen atoms or straight-chained or branched loweralkyl radicals or R³ and R⁴, together with the nitrogen atom to whichthey are attached, can also form a ring which optionally containsfurther heteroatoms; as well as the pharmacologically-acceptable saltsthereof.

Compounds of general formula (I) are preferred in which R¹ and R² arethe same or different and represent phenyl, pyridyl or thienyl ringswhich are either unsubstituted or are substituted by up to two halogenatoms, C₁ -C₄ alkoxy radicals, C₁ -C₄ dialkylamino radicals ortrifluoromethyl radicals, Alk is a straight-chained or branched C₁ -C₄alkylene chain and Z is a hydrogen atom, with the proviso that when Alkis a straight-chained alkylene chain, Z can also be an Amino radical ofthe general formula: ##STR5## in which R³ and R⁴ are the same ordifferent and are hydrogen atoms or methyl, ethyl, n-propyl or isopropylradicals or, together with the nitrogen atom to which they are attached,form a pyrrolidino, piperidino, morpholino or piperazino radical; aswell as the pharmacologically acceptable salts thereof.

Especially preferred are compounds of general formula (I) in which R¹and R² are the same or different and represent phenyl, 4-chlorophenyl,4-dimethylaminophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-pyridyl,3-pyridyl, 2-thienyl or 3-trifluoromethylphenyl radicals and Alk-Zrepresents a methyl, ethyl, isopropyl, aminoethyl, aminopropyl,ethylaminoethyl, diethylaminoethyl or diethylaminopropyl radical.Especially preferred are the compounds of Example 4a(2-(2-diethylaminoethylthio)-4-(4-dimethylaminophenyl)-5-oxo-4-(3-pyridyl)-2-pyrrolin-3-carbonitril),Example 4i(4-(4-dimethylaminophenyl)-2-methylthio-5-oxo-4-(3-pyridyl)-2-pyrrolin-3-carbonitril)and Example 4k(2-(3-diethylaminopropylthio)-4-(4-dimethylaminophenyl)-5-oxo-4-(3-pyridyl)-2-pyrrolin-3-carbonitril).

The present invention also provides a chemically novel process for thepreparation of the compounds of general formula (I), wherein a compoundof the general formula: ##STR6## in which R¹ and R² have the samemeanings as above, is rearranged in a solvent with a base to give acompound of the general formula: ##STR7## in which R¹ and R² have thesame meanings as above, and this subsequently reacted with a compound ofthe general formula:

    X--Alk--Z                                                  (V)

in which Z and Alk have the same meanings as above and X is a reactiveester or ether group, and the compound obtained of general formula (I)is subsequently, if desired, converted into a pharmacologicallyacceptable salt.

In the case of the reaction of a compound of general formula (III) witha base, which is preferably carried out in a polar solvent, for examplea low boiling point alcohol, at reflux temperature, a rearrangementtakes place with the formation of compounds of general formula (IV).

The solvent used is preferably a polar solvent, especially a loweralcohol, for example methanol, ethanol or n-butanol. The rearrangementreaction requires the presence of a strong base, the preferred basesincluding potassium hydroxide, potassium carbonate, sodium methanolate,sodium ethanolate and potassium tert.-butylate.

In most cases, the reaction time is from 5 to 30 minutes. The course ofthe reaction can be monitored by the clearly visible clarification ofthe initially mostly deep orange to yellow coloured reaction mixture.The rearrangement product can be isolated by careful acidification ofthe reaction mixture and used as such for the alkylation with a compoundof general formula (V).

Preferably, however, the rearrangement product is not isolated butrather reacted directly, in a kind of one-pot reaction, with anappropriate reactive ester or ether of general formula (V). According tothe present invention, the reactive ester groups are to be understood tobe halogen atoms or alkylsulphate, alkylsulphonate or arylsulphonateradicals. Especially preferred for this purpose are the correspondinghalides, sulphates, p-toluene-sulphonates andp-bromo-toluene-sulphonates. Dialkylaminoalkyl halides are preferablyused in the form of their hydrochlorides or hydrobromides. In this case,2 mole equivalents of base are used for the alkylation reaction. In thecase of using a trialkyloxonium salt, X signifies a dialkylether group.

The reaction products of general formula (I) crystallise out directly,after filtering off the precipitated alkali metal halide, from thefiltrate or are obtained after concentration of the reaction mixture andpartitioning of the residue between a water-immiscible organic solvent,for example methylene chloride, and water, after evaporation of theorganic phase and crystallisation of the evaporation residue from anappropriate solvent.

Bases which are difficult to crystallise can be converted intoappropriate acid-addition salts. As examples of acid-addition salts,there may be mentioned the salts of organic and inorganic acids, forexample, hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromicacid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid,citric acid, malic acid, salicylic acid, ascorbic acid, malonic acid,maleic acid and succinic acid. the salts are prepared in the usualmanner by reacting the bases with appropriate inorganic or organicacids.

The compounds of general formula (III) used as starting materials areobtained by reacting appropriately substituted benzils with2-cyanothioacetamide in the presence of catalytic amounts of a base, forexample triethylamine or piperidine, at ambient temperature or at refluxtemperature. The solvent used can be polar and is preferably chloroform,dichloromethane, methanol or ethanol. The reaction time is from 2 to 20hours.

The most yellow or orange coloured compounds of general formula (III)are precipitated during the reaction as hardly soluble precipitates andmay be isolated in known manner by filtration, washing and drying oncethe solvent is removed from the residue.

When using asymmetrical benzils, isomeric products of the generalformula (III) can be formed in which R¹ and R² are changed over.However, the subsequent rearrangement and alkylation leads to the sameend product of general formula (I). The benzils used are either known orcan be prepared by known procedures and methods, for example byoxidation of appropriate benzoins with cupric salts (cf. OrganicReactions, Volume IV, Chapter 5, page 269/1948 and Houben-Weyl, Volume7/2a, pages 653 and 751).

The compounds of general formula (I) display an activity whichrepresents a new principle in the therapy of inflammatory and ulcerativediseases. Hitherto, inflammation-inhibiting substances of thenon-steroidal antiphlogistic type frequently displayed an ulcerogenicside action. In contradistinction thereto, the compounds according tothe present invention display an exellent compatibility and a very goodinhibition of inflammation, while being surprisingly ulcer-protective.

The compounds of formula (I) may therefore be used in the therapy ofinflammation, without gastrointestual side effects exhibited by allknown compounds, they are also useful in the therapy of ulcers, due totheir ulcer-protective action whis is supported by the antiinflammatoryaction.

Due to the good compatibility of the compounds and depending upon thedegree of severity of the disease to be treated, the dosage in humans isof the order of 50 to 100 mg. in the case of a single dose administeredorally or parenterally. Correspondingly, the daily dose amounts to about100 to 2000 mg.

The compounds of general formula (I) according to the present inventioncan be administered orally or parenterally in liquid or solid form. Asinjection solution, it is especially preferred to use water whichcontains the additives usual in the case of injection solutions, such asstabilising agents, solubilising agents and buffers.

Examples of additives of this kind include tartrate and citrate buffers,ethanol, complex formers (such as ethylenediamine-tetraacetic acid andthe non-toxic salts thereof), as well as high molecular weight polymers(such as liquid polyethylene oxide) for viscosity regulation. Examplesof solid carrier materials include starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, high molecular weightfatty acids (such as stearic acid), gelatine, agar-agar, calciumphosphate, magnesium stearate, animal and vegetable fats and solid highmolecular weight polymers (such as polethylene glycol); compositionssuitable for oral administration can, if desired, additionally containflavouring and/or sweetening agents.

Consequently, the present invention also provides pharmaceuticalcompositions containing at least one compound according to the presentinvention, together with conventional additive and/or carrier materials.

The following experimental report describes the action of the compoundsof general formula (I) according to the present invention:

Investigation of the acute toxicity

Method:

The determination of the acute toxicity was carried out on male mice(NMRI) with a body weight of from 18 to 23 g. All the experimentalanimals fasted for 20 hours before commencement of the experiment. Waterwas available ad libitum. Each dosage grouping contained 4 animals. Thedosage sequence was logarithmic. The test compounds were administeredintragastrally as suspensions in 1% tragacanth slurry. The volumeadministered was 20 ml./kg. body weight. The animals were observed for atotal of 7 days.

Results:

The following Table gives the LD₅₀ values after a 7 day observationperiod of the animals:

    ______________________________________                                        Acute toxicity on mice                                                        Compound of   route of   LD.sub.50                                            Example No.   administration                                                                           mg/kg.                                               ______________________________________                                        4a            intragastral                                                                             800                                                  4b            "          400                                                  4d            "          1600                                                 4e            "          >1600                                                4g            "          1600                                                 4i            "          >1600                                                4k            "          300                                                  6c            "          >1600                                                6f            "          >1600                                                ______________________________________                                    

Investigation of the antiphlogistic action against carrageenin oedema inrats

Method:

The experimental animals used were male rats (SIV 50), fasting for 20hours, with a body weight of 110 to 160 g. Water was available adlibitum. After determination of the initial value of the paw volume ofthe right hind leg, the test substance was administered intragastrallyas a suspension in 1% tragacanth slurry. 10 animals were used per dosagegroup. The volume administered was 20 ml./kg. body weight. The pawvolume was measured by means of mercury displacement. 60 minutes afterintragastral administration of the test substances, 0.1 ml. of a 1%carrageenin solution was injected subplantarily into the right hind paw.

1 and 3 hours after injection of the carrageenin, the paw volume of theoedematous paw was measured. The increase of the paw volume of the testsubstance-treated animals after 3 hours was compared with that of thecontrol animals and the inhibition of the paw oedema by the testsubstance was calculated therefrom as a percentage.

Results:

The results obtained are summarised in the following Table:

    ______________________________________                                        Antiphlogistic action against carrageenin                                     oedema in rats                                                                Compound of dosage mg/kg                                                                             inhibition of the paw                                  Example No. intragastrally                                                                           volume in %                                            ______________________________________                                        4a           50        59                                                                 100        77                                                     4d           50        26                                                                 125        83                                                     4e           25        37                                                                  50        70                                                     4g           50        25                                                                 100        61                                                     6c          125         6                                                                 250        45                                                     6f          125        24                                                                 250        45                                                     ______________________________________                                    

The compounds set out in the above Table show, in the case of asimultaneously good oral compatibility, remarkable antiphlogisticproperties, the most effective compounds being those of Examples 4a and4e.

Investigation of the influence on gastric juice secretion in rats

Method:

According to the method described by H. Shay et al. (Gastroenterology,5, 43-61/1945), male rats (SIV 50) with a body weight of 160 to 200 g.were fasted for 48 hours before commencement of the experiment. Waterwas available to the animals ad libitum. The test substances wereadministered intragastrally as a suspension in 1% tragacanth slurry. Thevolume administered was 10 ml./kg. body weight. 8 animals were used perexperimental group. One hour after administration of the substance, apyloric ligature was applied under light ether narcosis. 4 hours afterthis intervention, the animals were sacrificed. The extirpated stomachwas opened up along the curvatura major and the volume of the secretionwas measured and compared with the data obtained from the control group.

Results:

The following Table summarises the results obtained:

    ______________________________________                                        Influence on gastric juice secretion                                          in rats                                                                       Compound of dosage in mg/kg                                                                            inhibition of gastric                                Example No. intragastral juice secretion in %                                 ______________________________________                                        4a          62.5         45                                                               125          64                                                               250          73                                                   4b          50           24                                                               100          63                                                               200          76                                                   4d          125          48                                                               250          76                                                   ______________________________________                                    

As shown by the above Table, for the mentioned test compounds, in thecase of Shay's method applied to rats, there was obtained anoutstanding, dosage-dependent inhibition of the gastric juice secretion.

Investigation of the ulcer-protective action on gastric ulcers in ratsinduced by indomethacin

Method:

The experimental animals used were male rats (SIV 50), fasted for 20hours, with a body weight of 170 to 220 g. Water was available adlibitum. The animals were simultaneously given intragastrally 40 mg./kg.indomethacin and the test substance in the form of a suspension in 0.8%"Methocel". The control animals only received the corresponding dosageof indomethacin. 10 animals were used for each experimental group. Thevolume administered was 10 ml./kg. body weight. 5 hours afteradministration, the animals were sacrificed. After removal of thestomach and opening along the curvatura major, this was investigatedwith a stereomagnifier for the presence of ulcers. The ulcers wereassessed according to the point scheme suggested by M. Chaumontet et al.(Arzneim. Forsch., 28, 2119/1978) and the ulcer index was calculatedtherefrom. The ulcer index of the animals treated with indomethacin andtest substance was compared with that of the control animals which hadonly been treated with indomethacin and the ulcer inhibition calculatedtherefrom as a percentage.

Results:

The results obtained are summarised in the following Table:

    ______________________________________                                        Ulcer-protective action of stomach ulcers in                                  rats induced by indomethacin                                                  Compound of dosage in mg/kg                                                                            ulcer inhibition                                     Example No. intragastral in %                                                 ______________________________________                                        4a          125          84                                                   4i           50          88                                                   4K           50          33                                                               100          94                                                   ______________________________________                                    

The compounds referred to in the above Table display remarkableulcer-protective properties, the compound of Example 4i giving anespecially favourable therapeutic quotient on the basis of its goodcompatibility.

The following Examples are given for the purpose of illustrating thepresent invention:

EXAMPLE 12-(2-Diethylaminoethylthio)-4,4-diphenyl-5-oxo-2-pyrroline-3-carbonitrile

10.2 g. 5-Hydroxy-4,5-diphenyl-2-thioxo-3-pyrroline-3-carbonitrile and9.7 g. anhydrous potassium carbonate are heated under reflux for 20minutes in 250 ml. ethanol. A solution of 6.0 g. 2-diethylaminoethylchloride in 50 ml. ethanol is then added dropwise thereto within thecourse of 10 minutes and boiling continued for 1 hour. The reactionmixture is poured on to ice and the precipitate obtained is filtered offand recrystallised from ethyl acetate. There are obtained 11.9 g. (87%of theory)2-(2-diethylaminoethylthio)-4,4-diphenyl-5-oxo-2-pyrroline-3-carbonitrilein the form of colourless crystals; m.p. 156°-157° C.

The 5-hydroxy-4,5-diphenyl-2-thioxo-3-pyrroline-3-carbonitrile used asstarting material is prepared in the following manner:

A mixture of 60.0 g. benzil, 28.6 g. cyanothioacetamide, 500 ml.methanol and 20 drops of piperidine is stirred at ambient temperaturefor 5 hours. Thereafter, the solvent is stripped off on a rotaryevaporator and the residue obtained is recrystallised from toluene.After drying in a vacuum at 0.1 mm.Hg and 80° C., the desired compoundis obtained in the form of yellow crystals; m.p. 195° C. (decomp.).

The following compounds are obtained in an analogous manner:

4,4-diphenyl-5-oxo-2-(2-piperidinoethylthio)-2-pyrroline-3-carbonitrile; m.p. 177°-178° C.;

2-(2-dimethylaminopropylthio)-4,4-diphenyl-5-oxo-2-pyrroline-3-carbonitrile;m.p. 250° C. (decomp.);

4,4-diphenyl-2-ethylthio-5-oxo-2-pyrroline-3-carbonitrile; m.p. 180° C.;

4,4-diphenyl-2-(2-morpholinoethylthio)-5-oxo-2-pyrroline-3-carbonitrile;m.p. 170° C.

EXAMPLE 24-(4-Chlorophenyl)-4-(4-dimethylaminophenyl)-2-ethylthio-5-oxo-2-pyrroline-3-carbonitrile

25.9 g.4-(4-Chlorophenyl)-5-(4-dimethylaminophenyl)-5-hydroxy-2-thioxo-3-pyrroline-3-carbonitrileand 19.3 g. anhydrous potassium carbonate are heated for 40 minutes in400 ml. ethanol. A solution of 7.6 g. ethyl bromide in 40 ml. ethanol isthen added dropwise thereto in the course of 15 minutes and boilingcontinued for 1 hour. After concentration of the reaction mixture, theresidue is partitioned between methylene chloride and water, the organicphase is separated off, the solvent is removed in a vacuum and theresidue is crystallised from ethanol. There are obtained 18 g. of4-(4-chlorophenyl)-4-(4-dimethylaminophenyl)-2-ethylthio-5-oxo-2-pyrroline-3-carbonitrilein the form of colourless crystals; m.p. 195° C.

The4-(4-chlorophenyl)-5-(4-dimethylaminophenyl)-5-hydroxy-2-thioxo-3-pyrroline-3-carbonitrileused asstarting material is prepared in the following manner:

A suspension of 60.0 g. p-dimethylamino-p'-chlorobenzil, 195 g.cyanothioacetamide and 1 ml. piperidine in 1 liter dichloromethane isstirred at ambient temperature for 20 hours. The precipitated product isfiltered off with suction, washed with dichloromethane andrecrystallised from ethanol. The desired product is obtained in a yieldof 61.9 g. in the form of yellow crystals; m.p. 189° C. (decomp.).

The following compounds are obtained in an analogous manner:

4-(4-chlorophenyl)-4-(4-dimethylaminophenyl)-2-(morpholinoethylthio)-5-oxo-2-pyrroline-3-carbonitrile;m.p. 215° C.;

4-(4-chlorophenyl)-4-(4-dimethylaminophenyl)-5-oxo-2-(2-piperidinoethylthio)-2-pyrroline-3-carbonitrile;m.p. 235° C. (decomp.);

4-(4-chlorophenyl)-2-(2-diethylaminoethylthio)-4-(4-dimethylaminophenyl)-5-oxo-2-pyrroline-3-carbonitrile;m.p. 196°-198° C.;

4-(4-chlorophenyl)-2-(3-dimethylaminopropylthio)-4-(4-dimethylaminophenyl)-5-oxo-2-pyrroline-3-carbonitrile;m.p. 180° C.;

2-(2-diethylaminoethylthio)-4-(4-dimethylaminophenyl)-5-oxo-4-phenyl-2-pyrroline-3-carbonitrile;m.p. 169° C.;

4-(4-dimethylaminophenylthio)-2-(2-morpholinoethylthio)-5-oxo-4-phenyl-2-pyrroline-3-carbonitrile;m.p. 209° C.;

2-(2-dimethylaminoethylthio)-4-(4-dimethylaminophenyl)-5-oxo-4-phenyl-2-pyrroline-3-carbonitrile;m.p. 172° C.;

4-(4-dimethylaminophenyl)-2-(2-piperidinoethylthio)-5-oxo-4-phenyl-2-pyrroline-3-carbonitrile;m.p. 184° C.;

4,4-bis-(4-chlorophenyl)-2-(2-diethylaminoethylthio)-5-oxo-2-pyrroline-3-carbonitrile;m.p. 166° C.;

2-(2-diethylaminoethylthio)-4,4-bis-(4-methoxyphenyl)-5-oxo-2-pyrroline-3-carbonitrile; m.p. 164° C.

The compounds used as starting materials are prepared as follows:

5-Hydroxy-4,5-bis-(4-methoxypenyl)-2-thioxo-3-pyrroline-3-carbonitrile

16.5 g. 4,4'-Dimethoxybenzil, 6.0 g. cyanothioacetamide and 15 drops ofpiperidine were boiled for 2 hours in 200 ml. chloroform on a waterseparator. The yellow precipitate obtained was filtered off withsuction, washed with some chloroform and dried at 80° C. and 0.1 mm.Hgfor 12 hours. The desired product is obtained in a yield of 17.6 g. inthe form of yellow crystals; m.p. 193° C. (decomp.).

4,5-Bis-(4-chlorophenyl)-5-hydroxy-2-thioxo-3-pyrroline-3-carbonitrile

A suspension of 22.3 g. 4,4'-dichlorobenzil, 6.5 g.2-cyanothioacetamide, 20 drops of piperidine and 200 ml. chloroform isstirred for 20 hours at ambient temperature. The yellow precipitateobtained is filtered off with suction, well washed with chloroform anddried. There are obtained 22.0 g. of the desired compound in the form ofyellow crystals; m.p. 213° C. (decomp.).

5-(4-Dimethylaminophenyl)-5-hydroxy-4-phenyl-2-thioxo-3-pyrroline-3-carbonitrile

A mixture of 10.1 g. p-dimethylaminobenzil, 3.2 g. cyanothioacetamide,10 drops of piperidine and 100 ml. ethanol is stirred for 12 hours atambient temperature. The precipitated product is filtered off withsuction, washed with chloroform and recrystallised from ethanol. Thereare obtained 6.0 g. of the desired product in the form of yellowcrystals; m.p. 184°-185° C. (decomp.).

EXAMPLE 32-(2-Diethylaminoethylthio)-5-oxo-4-phenyl-4-(3-trifluoromethylphenyl)-2-pyrroline-3-carbonitrile

19.5 g. 3-Trifluoromethylbenzil, 7.0 g. cyanothioacetamide, 0.5 ml.piperidine and 400 ml. chloroform are stirred for 20 hours at ambienttemperature. The yellow suspension is concentrated to about 100 ml. andthe yellow precipitate obtained is filtered off with suction, washed anddried. There are obtained 24.0 g. of yellow condensation product; m.p.200° C. (decomp.).

10.8 g. of the yellow condensation product and 8.3 g. potassiumcarbonate are boiled, while stirring, for 1 hour in 250 ml. ethanol. Asolution of 5.2 g. 2-diethylaminoethyl chloride hydrochloride in 50 ml.ethanol is then added dropwise thereto within the course of 10 minutes,boiling is continued for half an hour and the reaction mixture isfinally evaporated on a rotary evaporator. The residue is partitionedbetween methylene chloride and water and the organic phase is dried.After evaporation, there are obtained 17.5 g. of oily base.

12.6 g. of this base are dissolved in 350 ml. diethyl ether and slowlymixed with a solution of 2.5 g. oxalic acid in 50 ml. diethyl ether. Thecolourless precipitate obtained is filtered off with suction andrecrystallised from ethanol. There are obtained 7.6 g.2-(2-diethylaminoethylthio)-5-oxo-4-phenyl-4-(3-trifluoromethylphenyl)-2-pyrroline-3-carbonitrile inthe form of colourless crystals; m.p. 126° C.

2-(2-Diethylaminoethylthio)-4-(4-fluorophenyl)-5-oxo-4-phenyl-2-pyrroline-3-carbonitrile is obtained in an analogous manner: 16.0 g.4-fluorobenzil and 7.0 g. cyanothioacetamide give a yellow condensationproduct; m.p. 170°-185° C. 10.8 g. of this condensation product give,after crystallisation of the oily base from ethanol, 11.6 g. of thedesired product in the form of colourless crystals; m.p. 127° C.

EXAMPLE 4 2-(Diethylaminoethylthio)-4-(4-dimethylaminophenyl)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile (4a)

2.3 g. Sodium are dissolved in 300 ml. ethanol, 16.8 g.5-(4-dimethylaminophenyl)-5-hydroxy-4-(3-pyridyl)-2-thioxo-2-pyrroline-3-carbonitrileare added thereto and the reaction mixture is boiled for 30 minutes. Asolution of 8.6 g. diethylaminoethyl chloride hydrochloride in 50 ml.ethanol is then added dropwise thereto and boiling continued for 1 hour.The reaction mixture is then concentrated and water is added to the oilyresidue obtained, followed by extraction with methylene chloride. Theorganic phase is concentrated and the residue crystallised from ethanol,with the addition of some active charcoal. There are obtained 14.6 g.2-(2-diethylaminoethylthio)-4-(4-dimethylaminophenyl)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrilein the form of colourless crystals; m.p. 150° C.

The5-(4-dimethylaminophenyl)-5-hydroxy-4-(3-pyridyl)-2-thioxo-3-pyrroline-3-carbonitrileused as starting material is prepared in the following manner:

A suspension of 93.5 g. 3-pyridyl-4-dimethylaminophenylglyoxal, 35 g.cyanothioacetamide and 2 ml. piperidine in 1 liter methanol is stirredfor 20 hours at ambient temperature. The red precipitate obtained isfiltered off with suction, well washed with methanol and recrystallisedfrom ethanol. The desired compound is obtained in the form of redcrystals, the yield being 105.6 g.; m.p. 191° C. (decomp.).

The following compounds are obtained in an analogous manner:

4-(4-dimethylaminophenyl)-2-(2-morpholinoethylthio)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 149° C.; (4b)

4-(4-dimethylaminophenyl)-2-(3-dimethylaminopropylthio)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 152° C.; (4c)

4-(4-dimethylaminophenyl)-2-(2-piperidinoethylthio)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 180° C.; (4d)

4-(4-dimethylaminophenyl)-2-(2-pyrrolidinoethylthio)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 196° C.; (4e)

4-(4-dimethylaminophenyl)-5-oxo-2-(diisopropylaminoethylthio)-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 157° C.; (4f)

2-(2-dimethylaminoethylthio)-4-(4-dimethylaminophenyl)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 190° C.; (4g)

4-(4-dimethylaminophenyl)-5-oxo-2-propylthio-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 193° C.; (4h)

4-(4-dimethylaminophenyl)-2-methylthio-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 206° C.; (4i)

4-(4-dimethylaminophenyl)-2-(3-morpholinopropylthio)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 172° C.; (4j)

2-(3-diethylaminopropylthio)-4-(4-dimethylaminophenyl)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 134° C.; (4k)

4-(4-dimethylaminophenyl)-5-oxo-2-(2-piperazinoethylthio)-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;oxalate m.p. 130° C.; (4l)

4-(4-dimethylaminophenyl)-5-oxo-2-(3-piperidinopropylthio)-4-(3-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 168° C. (4m)

2-ethylthio-4-(4-dimethylaminophenyl)-5-oxo-4-(3-pyridyl)-2-pyrrolin-3-carbonitril;m.p. 213° C; (4n)

2-(2-aminoethylthio)-4-(4-dimethylaminophenyl-5-oxo-4-(3-pyridyl)-2-pyrrolin-3-carbonitril;m.p. 205°-206° C.; (4o)

2-(3-aminopropylthio)-4-(4-dimethylaminophenyl)-5-oxo-4-(3-pyridyl)-2-pyrrolin-3-carbonitril;m.p. 205°-208° C. (decomp.). (4p)

EXAMPLE 52-(2-Diethylaminoethylthio)-4-(4-fluorophenyl)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrilehydrochloride

27.2 g. 4-Fluorophenyl-3-pyridylglyoxal, 10.0 g. cyanothioacetamide, 10drops of piperidine and 500 ml. chloroform are stirred for 6 hours atambient temperature. The precipitated yellow product is filtered offwith suction, washed with some chloroform and dried at 60° C. There areobtained 28.2 g. of a yellow condensation product; m.p. 170°-172° C.(decomp.).

2.2 g. Sodium are dissolved in 250 ml. absolute ethanol, 15.0 g. of thecondensation product of 4-fluorophenyl-3-pyridylglyoxal andcyanothioacetamide are added thereto and the reaction mixture is boiledfor 15 minutes. A solution of 8.3 g. diethylaminoethyl chloridehydrochloride in 50 ml. ethanol is now added dropwise thereto in thecourse of 15 minutes and the reaction mixture thereafter heated underreflux for 4 hours. After cooling, the solvent is stripped off and theresidue is partitioned between chloroform and water. The driedchloroform phase is evaporated to dryness, the oily residue obtained istaken up in anhydrous diethyl ether/ethanol and the solution issaturated with dry hydrogen chloride. A precipitate initially obtainedagain goes into solution after a short time. The solvent is stripped offand the residue is triturated with diethyl ether. The solidified productis crystallised from isopropanol and finally again crystallised fromethanol with the addition of a few drops of water. There are obtained5.1 g. 2-(2-diethylaminoethylthio)-4-(4-fluorophenyl)-5- oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile hydrochloride in the form ofcolourless crystals; m.p. 247° C.

The following compounds are obtained in an analogous manner:

2-(2-Diethylaminoethylthio)-4-(4-methoxyphenyl)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile

12.0 g. 4-Methoxyphenyl-3-pyridylglyoxal and 5.0 g. cyanothioacetamidegive 15.8 g. of an orange-coloured product; m.p. 200° C. (decomp.). 10.0g. of condensation product give, after crystallisation from methanol,7.8 g. of the desired product in the form of colourless crystals; m.p.133° C.

2-(2-Diethylaminoethylthio)-5-oxo-4-phenyl-4-(3-pyridyl)-2-pyrroline-3-carbonitrile

20.0 g. Phenyl-3- pyridylglyoxal and 9.5 g. cyanothioacetamide give 23.7g. of a yellow condensation product; m.p. 140° C. (decomp.). 11.7 g. ofcondensation product give, after crystallisation from ethanol, 10.5 g.of the desired product in the form of colourless crystals; m.p. 133° C.

2-(2-Diethylaminoethylthio)-4-(3,4-dimethoxyphenyl)-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile

24.5 g. 3,4-Dimethoxyphenyl-3-pyridylglyoxal and 8.8 g.cyanothioacetamide give 30.0 g. of a yellow condensation product; m.p.175°-180° C. (decomp.) (crystallised from ethanol). 15.0 g. ofcondensation product give, after crystallisation from isopropanol, 10.5g. of the desired product in the form of colourless crystals; m.p.133°-135° C.

2-(2-Diethylaminoethylthio)-5-oxo-4-(3-pyridyl)-4-(3-trifluoromethylphenyl)-2-pyrroline-3-carbonitrileoxalate

22.9 g. 3-Pyridyl-3-trifluoromethylphenylglyoxal and 7.0 g.cyanothioacetamide give, after a reaction time of 12 hours, 19.3 g. ofyellow condensation product; m.p. 216° C. (decomp.). 19.0 g. ofcondensation product give 14.0 g. of oily base, the oxalate of which isprecipitated out from an ethereal solution. Yield 14.2 g. of the desiredproduct in the form of colourless crystals; m.p. 115° C. (decomp.)(recrystallised from ethanol).

EXAMPLE 62-(2-Diethylaminoethylthio)-5-oxo-4-phenyl-4-(2-thienyl)-2-pyrroline-3-carbonitrile(6a)

29.5 g. Benz-2-thenyl, 13.4 g. cyanothioacetamide, 0.5 ml. piperidineand 500 ml. methylene chloride are stirred for 20 hours at ambienttemperature. The precipitated product is filtered off with suction andcrystallised from ethanol. There are obtained 29.6 g. of greenishcrystals (m.p. 187°-189° C.). 14.9 g. of this condensation product ofbenz-2-thenyl and cyanothioacetamide, together with 13.8 g. potassiumcarbonate, are heated under reflux, while stirring, for 1 hour in 300ml. ethanol. A solution of 8.6 g. 2-diethylaminoethyl chloridehydrochloride in 100 ml. ethanol is added dropwise thereto within thecourse of 10 minutes and boiling continued for 45 minutes. The reactionmixture is concentrated, mixed with water and extracted with methylenechloride. The organic phase is evaporated and the residue crystallisedfrom ethanol. There are obtained 15.3 g.2-(2-diethylaminoethylthio)-5-oxo-4-phenyl-4-(2-thienyl)-2-pyrroline-3-carbonitrilein the form of colourless crystals; m.p. 165° C.

The following compounds are obtained in an analogous manner:

2-(2-ethylthio)-5-oxo-4-phenyl-4-(2-thienyl)-2-pyrroline-3-carbonitrile;m.p. 115° C.; (6b)

2-(2-morpholinoethylthio)-5-oxo-4-phenyl-4-(2-thienyl)-2-pyrroline-3-carbonitrile;m.p. 185°-186° C.; (6c)

2-(2-piperidinoethylthio)-5-oxo-4-phenyl-4-(2-thienyl)-2-pyrroline-3-carbonitrile;m.p. 180° C.; (6d)

2-(3-diethylaminopropylthio)-5-oxo-4-phenyl-4-(2-thienyl)-2-pyrroline-3-carbonitrile;m.p. 151° C.; (6e)

5-oxo-4-phenyl-2-(2-pyrrolidinoethylthio)-4-(2-thienyl)-2-pyrroline-3-carbonitrile.(6f)

EXAMPLE 72-(3-Dimethylaminopropylthio)-5-oxo-4,4-bis-(2-pyridyl)-2-pyrroline-3-carbonitrile

10.2 g.5-Hydroxy-4,5-bis-(2-pyridyl)-2-thioxo-3-pyrroline-3-carbonitrile and8.4 g. anhydrous potassium carbonate are heated under reflux for 30minutes in 250 ml. ethanol. A solution of 4.8 g. 3-dimethylaminopropylchloride hydrochloride in 30 ml. ethanol is added dropwise thereto andboiling continued for 1 hour. The reaction mixture is then evaporated ona rotary evaporator and the residue is mixed with water and extractedwith methylene chloride. The organic phase is dried over anhydroussodium sulphate, the solvent is stripped off and the oily residue iscrystallised from ethanol. There is obtained a yield of 63% of theory of2-(3-dimethylaminopropylthio)-5-oxo-4,4-bis-(2-pyridyl)-2-pyrroline-3-carbonitrilein the form of colourless crystals; m.p. 184°-185° C.

The 5-hydroxy-4,5-bis-(2-pyridyl)-2-thioxo-3-pyrroline-3-carbonitrileused as starting material is prepared in the following manner:

11.0 g. 2,2'-pyridyl and 5.0 g. cyanothioacetamide are dissolved in 200ml. absolute ethanol, 5 drops of piperidine are added thereto and thereaction mixture is heated under reflux for half an hour. After coolingto 0° C., the precipitate obtained is filtered off with suction, washedwith some ethanol and recrystallised from ethanol. The crystals obtainedare dried for 12 hours at 100° C. and 0.1 mm.Hg. Yield 9.8 g.; m.p. 188°C. (decomp.).

The following compounds are obtained in an analogous manner:

5-oxo-2-(2-piperidinoethylthio)-4,4-bis-(2-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 203°-204° C.;

2-(2-diethylaminoethylthio)-5-oxo-4,4-bis-(2-pyridyl)-2-pyrroline-3-carbonitrile;m.p.135°-136° C.;

2-(2-ethylthio)-5-oxo-4,4-bis-(2-pyridyl)-2-pyrroline-3-carbonitrile;m.p. 180° C.

EXAMPLE 8 4,4-Diphenyl-2-isopropylthio-5-oxo-2-pyrroline-3-carbonitrile

1.2 g. Sodium is dissolved in 150 ml. ethanol, 15.2 g.5-hydroxy-4,5-diphenyl-2-thioxo-3-pyrroline-3-carbonitrile are addedthereto and the reaction mixture is boiled for 20 minutes. Within thecourse of 10 minutes, a solution of 7.0 g. isopropyl bromide in 25 ml.absolute ethanol is then added dropwise thereto, followed by heatingunder reflux for a further 3 hours. After cooling, the solvent isstripped off on a rotary evaporator and the residue triturated with 100ml. water. The precipitate obtained is filtered off with suction andcrystallised from ethanol. There are obtained 11.1 g. (64% of theory)4,4-diphenyl-2-isopropylthio-5-oxo-2-pyrroline-3-carbonitrile in theform of colourless crystals; m.p. 160° C.

The 5-oxo-4,4-diphenyl-2-thioxopyrrolidine-3-carbonitrile of generalformula (IV) formed as intermediate is prepared as follows:

13.8 g. 5-Hydroxy-4,5-diphenyl-2-thioxo-3-pyrroline-3-carbonitrile areboiled for 15 minutes, while stirring, in 300 ml. ethanol with 12.4 g.potassium carbonate. The initially deep yellow solution soon becomeslighter and almost colourless. After cooling, the suspension is poured,with stirring, into 1 liter of ice water and acidified carefully withdilute hydrochloric acid. The precipitate obtained is filtered off withsuction and recrystallised from toluene. There are obtained 10.4 g. ofyellowish crystals; m.p. 170° C. (decomp.).

EXAMPLE 9 4,4-Diphenyl-2-isopropylthio-5-oxo-2-pyrroline-3-carbonitrile

1.2 g. Sodium is dissolved in 150 ml. ethanol, 15.2 g.5-hydroxy-4,5-diphenyl-2-thioxo-3-pyrroline-3-carbonitrile are addedthereto and the reaction mixture is then boiled for 20 minutes. Asolution of 7.0 g. isopropyl bromide in 25 ml. absolute ethanol is thenadded dropwise thereto within the course of 10 minutes and refluxingcontinued for a further 3 hours. After cooling, the solvent is strippedoff on a rotary evaporator and the residue is triturated with 100 ml.water. The precipitate is filtered off with suction and crystallisedfrom ethanol. There are obtained 11.1 g. (64.0% of theory) of thedesired product in the form of colourless crystals; m.p. 160° C.

2-Butylthio-4,4-diphenyl-5-oxo-2-pyrroline-3-carbonitrile is obtained inan analogous manner in a yield of 76% of theory.

EXAMPLE 104,4-Diphenyl-2-(1-methylpropylthio)-5-oxo-2-pyrroline-3-carbonitrile

0.8 g. Sodium is dissolved in 150 ml. absolute ethanol, 10.0 g.5-hydroxy-4,5-diphenyl-2-thioxo-3-pyrroline-3-carbonitrile are addedthereto and the reaction mixture is boiled for 30 minutes. The solventis thereafter removed on a rotary evaporator and the residue is taken upin 100 ml. dimethylformamide. 5.1 g. sec.-Butyl bromide are addedthereto, the reaction mixture is stirred for 24 hours at ambienttemperature, a further 3.0 g. of the alkylating agent are again addedthereto and stirring is continued for 24 hours. Thereafter, the solventis distilled off under water pump vacuum and the residue is trituratedwith water. The precipitate is filtered off with suction, washed withwater and crystallised from ethanol. There are obtained 7.0 g. of thedesired product in the form of colourless crystals; m.p. 155°-156° C.

We claim:
 1. A compound of the formula ##STR8## wherein R₁ is phenyl, R₂is thienyl, or R₁ and R₂ are both thienyl, in which rings are optionallysubstituted by up to two halogen atoms, C₁₋₄ -alkoxy radicals, C₁₄-dialkylamino radicals or trifluoromethyl radicals, Alk is astraight-chained or branched C₁₋₄ -alkylene chain, and Z is a hydrogenatom, with the provisional that when Alk is a straight-chain alkylene, Zcan also be an amino radical of the formula: ##STR9## in which R₃ and R₄are the same or different and are hydrogen atoms or methyl, ethyl,n-propyl or isopropyl radicals, or together with a nitrogen atom towhich they attached form a pyrrolidino, piperidino, morophilino, orpiperazino radical.
 2. A pharmaceutical composition comprising acompound according to claim 1, in admixture with a pharmaceuticalcarrier and/or adjuvant.
 3. A method of treating inflammation andgastrointestinal ulcers which comprises administering orally orparenterally to a host suffering therefrom an effective amount of apharmaceutical composition according to claim 2.